At present, a surgery, a percutaneous therapeutic method of utilizing ultrasound or electromagnetic waves, and a transcatheter therapeutic method are employed as a method for treatment of cancer. These methods can selectively remove and kill cancer cells to make the methods useful for topical control, and are expected to exert further topical control capability.
However, nevertheless their topical control capability, these methods are not sufficient to improve prognosis at the current situation. One possible reason is that repeated treatment with these methods influences normal cells around cancer cells, and thereby causes deterioration in functions of organs (in the case of a liver, deterioration in hepatic preliminary performance). A primal requisite for cancer treatment in the future is to inhibit growth of cancer cells, to inhibit angiogenesis and in the case of hepatic cancer to inhibit intraportal infiltration that is a prognostic prescribed factor, and to maintain the functions of organs (hepatic preliminary performance) simultaneously.
hepatocellular carcinoma is often developed from cirrhosis hepatic C or B, and often shows a reduction in hepatic preliminary performance. Hepatic cancer readily recurs due to blood-mediated metastases (intrahepatic metastases, vascular infiltration) or development of new hepatic cancer (multicentric carcinogenesis), and is known to have a poor prognosis as a 3-year survival rate of 52.5% and a 5-year survival rate of 35.4% according to a report of 2003. These current methods for treatment of hepatic cancer are considered to have problems of such as incomplete inhibition of multicentric carcinogenesis, difficulties in control of intraportal infiltration, and impossible treatment of deterioration in hepatic functional reserve. With the aging of hepatic cancer patients, less-invasive therapies have been demanded.
Fibroblast growth factor receptor (referred to hereinafter as “FGFR”) is a one-transmembrane receptor, and in mammals, there are 5 types of the receptors FGFR1 to FGFR4 and FGFR5/1L. Each of these FGFRs consists of extracellular 3 immunoglobulin (Ig)-like domains, a transmembrane domain, and intracellular 2 tyrosine kinase domains. The FGFR binds to FGF with two of the 31 g-like domains (Ig-like domains II and III), and thereby forms a dimer. FGFR undergoes selective splicing to produce many transcripts which gives FGFR ligand specificity.
Among these FGFRs, FGFR1 has been confirmed to be expressed in hepatic cancer and known to promote the development of hepatic cancer accompanying carcinogenic stimulation (Non-Patent Document 1). It has been reported that FGFR1 is not expressed in noncancerous hepatic cells (Non-Patent Document 2) and that FGFR1-mediated stimulation is involved not only in cell growth and cell infiltration but also in angiogenesis (Non-Patent Document 3).
From these findings, FGFR1 has been attractive target for cancer therapy. Particularly, FGFR1 has high affinity for bFGF which involved in angiogenesis, and has thus been considered as a molecular target of an anticancer agent. It has been revealed that amino acid sequence of African clawed frog (Xenopus laevis) FGFR1 has 74% and 80% homologies to that of human FGFR1 and mouse FGFR1, respectively, by Swiss plot comparative analysis and the like. A vaccine therapy with Xenopus laevis FGFR1 showed an anticancer effect, however vaccine therapy with mouse FGFR1 did not show an anticancer effect. Besides, antibodies to FGFR1 and the like have been already reported, however no effective anti-cancer drug targeting FGFR1 have been found yet.
Interferon is a cytokine known to be involved in growth inhibition of viruses and cells and in inflammatory reactions. Interferon is known to have types of type I interferon such as interferon-alpha and interferon-beta and type II interferon such as interferon-gamma. Interferon-gamma is known as a cytokine that inhibits growth and fibrillization of a human hepatic stellate cell which is known to contribute to development and progress of liver fibrosis. It is reported that, from cDNA microarray analysis, stimulation of human hepatic stellate cells with interferon-gamma reduces expression of FGFR1 (Non-Patent Document 4).
Non-Patent Document 1: Ectopic Activity of Fibroblast Growth Factor Receptor 1 in Hepatocytes Accelerates Hepatocarcinogenesis by Driving Proliferation and Vascular Endothelial Growth Factor; Induced Angiogenesis, Cancer Res 2006; 66(3): 1481-90
Non-Patent Document 2: Expressions of Basic Fibroblast Growth Factor and Its Receptors and Their Relationship to Proliferation of Human Hepatocellular Carcinoma Cell Lines, HEPATOLOGY 1996; 24: 198-205.
Non-Patent Document 3: THE ANTI-ANGIOGENIC ACTIVITY OF rPAI-123 INHIBITS FIBROBLAST GROWTH FACTOR-2 FUNCTIONS, JBC Papers in Press. Published on Sep. 1, 2006 as Manuscript M607097200
Non-Patent Document 4: Interferon-gamma down-regulates expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats, International journal of molecular medicine 17: 605-616, 2006